U.S. patent application number 13/122983 was filed with the patent office on 2011-09-22 for 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivatives useful as modulators of nicotinic acetylcholine receptors.
This patent application is currently assigned to NEUROSEARCH A/S. Invention is credited to Jeppe Kejser Christensen, Antonio Nardi, Dan Peters.
Application Number | 20110230485 13/122983 |
Document ID | / |
Family ID | 41600592 |
Filed Date | 2011-09-22 |
United States Patent
Application |
20110230485 |
Kind Code |
A1 |
Nardi; Antonio ; et
al. |
September 22, 2011 |
6-PHENYL-PYRIMIDIN-4-YL-(PHENYLAMINE OR PHENOXY) DERIVATIVES USEFUL
AS MODULATORS OF NICOTINIC ACETYLCHOLINE RECEPTORS
Abstract
This invention relates to novel
6-phenyl-phymidin-4-yl-(phenylannine or phenoxy) derivatives, which
are found to be modulators of the nicotinic acetylcholine
receptors. Due to their pharmacological profile the compounds of
the invention may be useful for the treatment of diseases or
disorders as diverse as those related to the cholinergic system of
the central nervous system (CNS), the peripheral nervous system
(PNS), diseases or disorders related to smooth muscle contraction,
endocrine diseases or disorders, diseases or disorders related to
neuro-degeneration, diseases or disorders related to inflammation,
pain, and withdrawal symptoms caused by the termination of abuse of
chemical substances.
Inventors: |
Nardi; Antonio;
(Herzogenrath, DE) ; Christensen; Jeppe Kejser;
(Glostrup, DK) ; Peters; Dan; (Malmo, SE) |
Assignee: |
NEUROSEARCH A/S
Ballerup
DK
|
Family ID: |
41600592 |
Appl. No.: |
13/122983 |
Filed: |
October 9, 2009 |
PCT Filed: |
October 9, 2009 |
PCT NO: |
PCT/EP09/63168 |
371 Date: |
May 17, 2011 |
Current U.S.
Class: |
514/235.8 ;
514/256; 514/269; 544/123; 544/319; 544/326; 544/327; 544/328 |
Current CPC
Class: |
A61P 21/00 20180101;
C07D 413/12 20130101; A61P 9/12 20180101; A61P 15/00 20180101; A61P
17/10 20180101; A61P 25/00 20180101; A61P 25/04 20180101; A61P
25/28 20180101; C07D 405/12 20130101; A61P 5/00 20180101; A61P
25/36 20180101; C07D 239/42 20130101; A61P 25/18 20180101; A61P
25/24 20180101; C07D 403/12 20130101; A61P 25/14 20180101; A61P
9/06 20180101; A61P 3/04 20180101; A61P 25/22 20180101; A61P 25/16
20180101; A61P 1/12 20180101; A61P 11/06 20180101; A61P 25/20
20180101; A61P 29/00 20180101; A61P 25/08 20180101; A61P 43/00
20180101; A61P 17/00 20180101; A61P 25/30 20180101; C07D 239/34
20130101; A61P 25/06 20180101 |
Class at
Publication: |
514/235.8 ;
544/326; 544/328; 544/327; 544/319; 544/123; 514/256; 514/269 |
International
Class: |
A61K 31/5377 20060101
A61K031/5377; C07D 239/48 20060101 C07D239/48; C07D 401/12 20060101
C07D401/12; C07D 403/12 20060101 C07D403/12; C07D 405/12 20060101
C07D405/12; C07D 239/47 20060101 C07D239/47; C07D 413/12 20060101
C07D413/12; A61K 31/505 20060101 A61K031/505; A61K 31/506 20060101
A61K031/506; A61P 25/22 20060101 A61P025/22; A61P 25/00 20060101
A61P025/00; A61P 25/28 20060101 A61P025/28; A61P 25/16 20060101
A61P025/16; A61P 25/24 20060101 A61P025/24; A61P 25/18 20060101
A61P025/18; A61P 3/04 20060101 A61P003/04; A61P 25/20 20060101
A61P025/20; A61P 25/14 20060101 A61P025/14; A61P 25/08 20060101
A61P025/08; A61P 43/00 20060101 A61P043/00; A61P 9/12 20060101
A61P009/12; A61P 9/06 20060101 A61P009/06; A61P 21/00 20060101
A61P021/00; A61P 1/12 20060101 A61P001/12; A61P 11/06 20060101
A61P011/06; A61P 15/00 20060101 A61P015/00; A61P 5/00 20060101
A61P005/00; A61P 25/04 20060101 A61P025/04; A61P 25/06 20060101
A61P025/06; A61P 29/00 20060101 A61P029/00; A61P 17/00 20060101
A61P017/00; A61P 17/10 20060101 A61P017/10; A61P 25/30 20060101
A61P025/30; A61P 25/36 20060101 A61P025/36 |
Foreign Application Data
Date |
Code |
Application Number |
Oct 9, 2008 |
DK |
PA 2008 01421 |
May 12, 2009 |
DK |
PA 2009 00604 |
Claims
1. A 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
represented by Formula I ##STR00010## a stereoisomer thereof or a
mixture of its stereoisomers, or a pharmaceutically acceptable salt
thereof, wherein X represents O or NH; Y represents CH or N; R'
represents hydrogen or alkyl; R.sup.1 and R.sup.2, independently of
each other, represent a substituent selected from the group
consisting of hydrogen, halo, trifluoromethyl, trifluoromethoxy,
nitro, cyano and hydroxy; R.sup.3 represents amino or nitro; and
R.sup.4 and R.sup.5, independently of each other, represent
hydrogen, halo, trifluoromethyl, hydroxy, alkoxy, thioalkoxy,
cycloalkoxy, alkyl, cycloalkyl, sulfamoyl, piperidinyl,
morpholinyl, or pyridinyl; or R.sup.4 and R.sup.5 together with the
phenyl ring to which they are attached form a methylenedioxy group
or ethylenedioxy group; or R.sup.4 and R.sup.5 together with the
phenyl ring to which they are attached form a bicyclic carbocyclic
ring selected from naphthyl and tetrahydronaphthalenyl; or R.sup.4
and R.sup.5 together with the phenyl ring to which they are
attached form a bicyclic heterocyclic ring selected from indolyl,
indazolyl, quinolinyl and isoquinolinyl.
2. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein X represents O or NH.
3. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein Y represents CH or N.
4. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein R' represents hydrogen or alkyl.
5. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein R.sup.1 and R.sup.2, independently of each other, represent
a substituent selected from the group consisting of hydrogen, halo,
trifluoromethyl, trifluoromethoxy, nitro, cyano and hydroxy.
6. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein R.sup.3 represents amino or nitro.
7. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein R.sup.4 and R.sup.5, independently of each other, represent
hydrogen, halo, trifluoromethyl, hydroxy, alkoxy, thioalkoxy,
cycloalkoxy, alkyl, cycloalkyl, sulfamoyl, piperidinyl,
morpholinyl, or pyridinyl.
8. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein R.sup.4 and R.sup.5 together with the phenyl ring to which
they are attached form a methylenedioxy group or ethylenedioxy
group.
9. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein R.sup.4 and R.sup.5 together with the phenyl ring to which
they are attached form a bicyclic carbocyclic ring selected from
naphthyl and tetrahydronaphthalenyl.
10. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable salt thereof,
wherein R.sup.4 and R.sup.5 together with the phenyl ring to which
they are attached form a bicyclic heterocyclic ring selected from
indolyl, indazolyl, quinolinyl and isoquinolinyl.
11. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, which is
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(4-methoxy-
-phenyl)-amine;
4-[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-ylamino]-phe-
nol;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(4-methoxy-phenyl)-pyrimid-
ine-4,5-diamine;
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-phe-
nol;
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(6-met-
hoxy-pyridin-3-yl)-amine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(6-methoxy-pyridin-3-yl)-pyrim-
idine-4,5-diamine;
4-[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-ylamino]-ben-
zenesulfonamide;
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-ben-
zenesulfonamide;
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(1H-indol--
5-yl)-amine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(1H-indol-5-yl)-pyrimidine-4,5-
-diamine;
5-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-yla-
mino]-pyridin-2-ol;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(1H-indazol-5-yl)-pyrimidine-4-
,5-diamine;
N*4*-Benzo[1,3]dioxol-5-yl-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidi-
ne-4,5-diamine;
N*4*-(4-Cyclopropylmethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)--
pyrimidine-4,5-diamine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-naphthalen-1-yl-pyrim-
idine-4,5-diamine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(4-methoxy-phenyl)-2-methyl-py-
rimidine-4,5-diamine;
N*4*-(2,4-Difluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidine-4,5-diamine
N*4*-(4-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyr-
imidine-4,5-diamine;
N*4*-(2-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyr-
imidine-4,5-diamine;
N*4*-(2,4-Dichloro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidine-4,5-diamine;
N*4*-Benzo[1,3]dioxol-5-yl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidine-4,5-diamine;
N*4*-(3,5-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methy-
l-pyrimidine-4,5-diamine;
N*4*-(4-Chloro-3-trifluoromethyl-phenyl)-6-(2-fluoro-4-trifluoromethyl-ph-
enyl)-2-methyl-pyrimidine-4,5-diamine;
N*4*-(3-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyr-
imidine-4,5-diamine;
N*4*-(4-Cyclohexyl-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidine-4,5-diamine;
N*4*-(4-Ethoxy-phenyl)-6-(2-fluoro-4-bifluoromethyl-phenyl)-2-methyl-pyri-
midine-4,5-diamine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-p-tolyl-pyrimidine-4,-
5-diamine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-isoquinolin-5-yl-2-m-
ethyl-pyrimidine-4,5-diamine;
N*4*-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-6-(2-fluoro-4-trifluoromethyl-ph-
enyl)-2-methyl-pyrimidine-4,5-diamine;
N*4*-(3,4-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methy-
l-pyrimidine-4,5-diamine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(3-methoxy-phenyl)-2-methyl-py-
rimidine-4,5-diamine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-(3-methylsulfanyl-phe-
nyl)-pyrimidine-4,5-diamine;
N*4*-(2,4-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methy-
l-pyrimidine-4,5-diamine;
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-naphthalen-2-yl-pyrim-
idine-4,5-diamine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-5-nitro-pyrim-
idine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-pyrimid-
in-5-ylamine;
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxy]-pheno-
l;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-propyl-phenoxy)-pyr-
imidin-5-ylamine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-morpholin-4-yl-phenox-
y)-pyrimidin-5-ylamine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(quinolin-8-yloxy)-pyrim-
idin-5-ylamine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(5,6,7,8-tetrahydro-naph-
thalen-2-yloxy)-pyrimidin-5-ylamine;
4-(4-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrim-
idin-5-ylamine;
4-(Benzo[1,3]dioxol-5-yloxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-meth-
yl-pyrimidin-5-ylamine;
4-(2-Chloro-4-methoxy-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-me-
thyl-pyrimidin-5-ylamine;
4-(3-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrim-
idin-5-ylamine;
4-(2-Chloro-4-trifluoromethyl-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phen-
yl)-2-methyl-pyrimidin-5-ylamine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-2-methyl-pyri-
midin-5-ylamine;
4-(3-Chloro-5-methoxy-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-me-
thyl-pyrimidin-5-ylamine;
4-(3-tert-Butyl-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-p-
yrimidin-5-ylamine;
4-(4-tert-Butyl-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-p-
yrimidin-5-ylamine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-piperidin-1-yl-phenox-
y)-pyrimidin-5-ylamine;
4-(2-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrim-
idin-5-ylamine; or
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-phenoxy-pyrimidin-5-ylam-
ine; a stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof.
12. A pharmaceutical composition comprising a therapeutically
effective amount of a 6-phenyl-pyrimidin-4-yl-(phenylamine or
phenoxy) derivative of claim 1, a stereoisomer thereof or a mixture
of its stereoisomers, or a pharmaceutically acceptable addition
salt thereof, together with at least one pharmaceutically
acceptable carrier or diluent.
13. The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of claim 1, a stereoisomer thereof or a mixture of its
stereoisomers, or a pharmaceutically acceptable addition salt
thereof, for use as a medicament.
14-16. (canceled)
17. A method of treatment, prevention or alleviation of a disease
or a disorder or a condition of a living animal body, including a
human, which disorder, disease or condition is responsive to
modulation of nicotinic acetylcholine receptors, which method
comprises the step of administering to such a living animal body in
need thereof a therapeutically effective amount of a
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of
claim 1, a stereoisomer thereof or a mixture of its stereoisomers,
or a pharmaceutically acceptable salt thereof.
18. The method according to claim 17, wherein the disease, disorder
or condition responsive to modulation of nicotinic acetylcholine
receptors is anxiety, a cognitive disorder, a learning deficit, a
memory deficit or dysfunction, Alzheimer's disease, attention
deficit, attention deficit hyperactivity disorder, Parkinson's
disease, Huntington's disease, Amyotrophic Lateral Sclerosis,
Gilles de la Tourette's syndrome, depression, mania, manic
depression, psychosis, schizophrenia, obsessive compulsive
disorders (OCD), panic disorders, an eating disorder including
anorexia nervosa, bulimia and obesity, narcolepsy, nociception,
AIDS-dementia, senile dementia, periferic neuropathy, autism,
dyslexia, tardive dyskinesia, hyperkinesia, epilepsy,
post-traumatic syndrome, social phobia, a sleeping disorder, pseudo
dementia, Ganser's syndrome, pre-menstrual syndrome, late luteal
phase syndrome, chronic fatigue syndrome, mutism, trichotillomania,
jet-lag, hypertension, cardiac arrhythmias, a smooth muscle
contraction disorder including convulsive disorders, angina
pectoris, premature labour, convulsions, diarrhoea, asthma,
epilepsy, tardive dyskinesia, hyperkinesia, premature ejaculation
and erectile difficulty, an endocrine system disorder including
thyrotoxicosis and pheochromocytoma, a neurodegenerative disorder,
including transient anoxia and induced neuro-degeneration, pain,
mild, moderate or severe pain, acute pain, chronic pain, pain of
recurrent character, neuropathic pain, pain caused by migraine,
postoperative pain, phantom limb pain, neuropathic pain, chronic
headache, central pain, pain related to diabetic neuropathy, to
post therapeutic neuralgia or to peripheral nerve injury, an
inflammatory disorder, including an inflammatory skin disorder,
acne, rosacea, Crohn's disease, inflammatory bowel disease,
ulcerative colitis and diarrhoea, a disorder associated with
withdrawal symptoms caused by termination of use of addictive
substances, including nicotine withdrawal symptoms, opioid
withdrawal symptoms, including heroin, cocaine and morphine,
benzodiazepine withdrawal symptoms including benzodiazepine-like
drugs and alcohol.
Description
TECHNICAL FIELD
[0001] This invention relates to novel
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivatives, which
are found to be modulators of the nicotinic acetylcholine
receptors. Due to their pharmacological profile the compounds of
the invention may be useful for the treatment of diseases or
disorders as diverse as those related to the cholinergic system of
the central nervous system (CNS), the peripheral nervous system
(PNS), diseases or disorders related to smooth muscle contraction,
endocrine diseases or disorders, diseases or disorders related to
neuro-degeneration, diseases or disorders related to inflammation,
pain, and withdrawal symptoms caused by the termination of abuse of
chemical substances.
BACKGROUND ART
[0002] The endogenous cholinergic neurotransmitter, acetylcholine,
exert its biological effect via two types of cholinergic receptors,
the muscarinic Acetyl Choline Receptors (mAChR) and the nicotinic
Acetyl Choline Receptors (nAChR).
[0003] As it is well established that muscarinic acetylcholine
receptors dominate quantitatively over nicotinic acetylcholine
receptors in the brain area important to memory and cognition, and
much research aimed at the development of agents for the treatment
of memory related disorders have focused on the synthesis of
muscarinic acetylcholine receptor modulators.
[0004] Recently, however, an interest in the development of nAChR
modulators has emerged. Several diseases are associated with
degeneration of the cholinergic system i.e. senile dementia of the
Alzheimer type, vascular dementia and cognitive impairment due to
the organic brain damage disease related directly to
alcoholism.
[0005] WO 99001439 describes aryl- and arylamino-substituted
heterocyclic compounds useful as corticotropin releasing hormone
antagonists. However, the 6-phenyl-pyrimidin-4-yl-(phenylamine or
phenoxy) derivatives of the present invention, or their use as
modulators of the nicotinic acetylcholine receptors, are not
suggested.
[0006] WO 2005 009977 describes substituted pyrimidin-4-yl-amine
analogs useful as vanilloid receptor ligands. However, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivatives of the
present invention, or their use as modulators of the nicotinic
acetylcholine receptors, are not suggested.
[0007] Hauser et al. [Hauser D R J.; Scior T; Domeyer D M.;
Kammerer B; Laufer S A; Journal of Medicinal Chemistry 2007 50 (9)
2060-2066] describes the synthesis, biological testing and binding
mode prediction of 6,9-Diarylpurin-8-ones useful as p38 MAP Kinase
Inhibitors. However, the 6-phenyl-pyrimidin-4-yl-(phenylamine or
phenoxy) derivatives of the present invention, or their use as
modulators of the nicotinic acetylcholine receptors, are not
suggested.
SUMMARY OF THE INVENTION
[0008] The present invention is devoted to the provision novel
modulators of the nicotinic receptors, which modulators are useful
for the treatment of diseases or disorders related to the
cholinergic receptors, and in particular the nicotinic
acetylcholine .alpha.7 receptor subtype.
[0009] The compounds of the invention may also be useful as
diagnostic tools or monitoring agents in various diagnostic
methods, and in particular for in vivo receptor imaging
(neuroimaging), and they may be used in labelled or unlabelled
form.
[0010] In its first aspect the invention provides
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivatives
represented by Formula I
##STR00001##
[0011] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof, wherein
[0012] X represents O or NH;
[0013] Y represents CH or N;
[0014] R' represents hydrogen or alkyl;
[0015] R.sup.1 and R.sup.2, independently of each other, represent
a substituent selected from the group consisting of hydrogen, halo,
trifluoromethyl, trifluoromethoxy, nitro, cyano and hydroxy;
[0016] R.sup.3 represents amino or nitro; and
[0017] R.sup.4 and R.sup.5, independently of each other, represent
hydrogen, halo, trifluoromethyl, hydroxy, alkoxy, thioalkoxy,
cycloalkoxy, alkyl, cycloalkyl, sulfamoyl, piperidinyl,
morpholinyl, or pyridinyl; or R.sup.4 and R.sup.5 together with the
phenyl ring to which they are attached form a methylenedioxy group
or ethylenedioxy group; or R.sup.4 and R.sup.5 together with the
phenyl ring to which they are attached form a bicyclic carbocyclic
ring selected from naphthyl and tetrahydronaphthalenyl; or R.sup.4
and R.sup.5 together with the phenyl ring to which they are
attached form a bicyclic heterocyclic ring selected from indolyl,
indazolyl, quinolinyl and isoquinolinyl.
[0018] In a second aspect the invention provides pharmaceutical
compositions comprising a therapeutically effective amount of the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention, or a pharmaceutically acceptable addition salt thereof,
together with at least one pharmaceutically acceptable carrier or
diluent.
[0019] Viewed from another aspect the invention relates to the use
of the 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
of the invention, or a pharmaceutically acceptable addition salt
thereof, for the manufacture of pharmaceutical
compositions/medicaments for the treatment, prevention or
alleviation of a disease or a disorder or a condition of a mammal,
including a human, which disease, disorder or condition is
responsive to modulation of cholinergic receptors.
[0020] In yet another aspect the invention provides a method for
treatment, prevention or alleviation of diseases, disorders or
conditions of a living animal body, including a human, which
disorder, disease or condition is responsive to modulation of
cholinergic receptors, and which method comprises the step of
administering to such a living animal body in need thereof a
therapeutically effective amount of the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention.
[0021] Other objects of the invention will be apparent to the
person skilled in the art from the following detailed description
and examples.
DETAILED DISCLOSURE OF THE INVENTION
6-Phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivatives
[0022] In its first aspect the invention provides
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivatives
represented by Formula I
##STR00002##
[0023] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof, wherein
[0024] X represents O or NH;
[0025] Y represents CH or N;
[0026] R' represents hydrogen or alkyl;
[0027] R.sup.1 and R.sup.2, independently of each other, represent
a substituent selected from the group consisting of hydrogen, halo,
trifluoromethyl, trifluoromethoxy, nitro, cyano and hydroxy;
[0028] R.sup.3 represents amino or nitro; and
[0029] R.sup.4 and R.sup.5, independently of each other, represent
hydrogen, halo, trifluoromethyl, hydroxy, alkoxy, thioalkoxy,
cycloalkoxy, alkyl, cycloalkyl, sulfamoyl, piperidinyl,
morpholinyl, or pyridinyl; or R.sup.4 and R.sup.5 together with the
phenyl ring to which they are attached form a methylenedioxy group
or ethylenedioxy group; or R.sup.4 and R.sup.5 together with the
phenyl ring to which they are attached form a bicyclic carbocyclic
ring selected from naphthyl and tetrahydronaphthalenyl; or R.sup.4
and R.sup.5 together with the phenyl ring to which they are
attached form a bicyclic heterocyclic ring selected from indolyl,
indazolyl, quinolinyl and isoquinolinyl.
[0030] In a more preferred embodiment, the invention provides a
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
represented by Formula Ia
##STR00003##
[0031] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof, wherein
[0032] X represents O or NH;
[0033] Y represents CH or N;
[0034] R.sup.1 and R.sup.2, independently of each other, represent
a substituent selected from the group consisting of hydrogen, halo,
trifluoromethyl, trifluoromethoxy, nitro, cyano and hydroxy;
[0035] R.sup.3 represents amino or nitro; and
[0036] R.sup.4 and R.sup.5, independently of each other, represent
hydrogen, hydroxy, alkoxy, sulfamoyl or pyridinyl; or R.sup.4 and
R.sup.5 together with the phenyl ring to which they are attached
form a bicyclic heterocyclic ring selected from indolyl and
indazolyl.
[0037] In another more preferred embodiment, the invention provides
a 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
represented by Formula Ib
##STR00004##
[0038] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof, wherein
[0039] X represents O or NH; and
[0040] R.sup.1, R.sup.2, R.sup.3, R.sup.4 and R.sup.5, are as
defined above. In a third more preferred embodiment, the invention
provides a 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy)
derivative represented by Formula Ic
##STR00005##
[0041] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof, wherein
[0042] R.sup.1 and R.sup.2, independently of each other, represent
a substituent selected from the group consisting of hydrogen, halo,
trifluoromethyl, trifluoromethoxy, nitro, cyano and hydroxy;
[0043] R.sup.3 represents amino or nitro; and
[0044] R.sup.4 and R.sup.5, independently of each other, represent
hydrogen, hydroxy, alkoxy, sulfamoyl or pyridinyl; or R.sup.4 and
R.sup.5 together with the phenyl ring to which they are attached
form a bicyclic heterocyclic ring selected from indolyl and
indazolyl.
[0045] In a third more preferred embodiment, the invention provides
a 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
represented by Formula Id
##STR00006##
[0046] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof, wherein
[0047] X represents O or NH;
[0048] Y represents CH or N;
[0049] R.sup.1, R.sup.2 and R.sup.3 are as defined above; and
[0050] R.sup.4 represents hydroxy, alkoxy, sulfamoyl or
pyridinyl.
[0051] In a fifth more preferred embodiment, the invention provides
a 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative
represented by Formula Ie
##STR00007##
[0052] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof, wherein
[0053] R.sup.1, R.sup.2 and R.sup.3 are as defined above; and
[0054] R.sup.4 represents hydroxy, alkoxy, sulfamoyl or
pyridinyl.
[0055] In another preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein X represents O or
NH.
[0056] In a more preferred embodiment, X represents O.
[0057] In another more preferred embodiment, X represents NH.
[0058] In a third preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein Y represents CH
or N.
[0059] In a more preferred embodiment, Y represents CH.
[0060] In another more preferred embodiment, Y represents N.
[0061] In a fourth preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of f
the invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein R' represents
hydrogen or alkyl.
[0062] In a more preferred embodiment, R' represents hydrogen.
[0063] In another more preferred embodiment, R' represents alkyl,
and in particular methyl.
[0064] In a fifth preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.1 and
R.sup.2, independently of each other, represent a substituent
selected from the group consisting of hydrogen, halo,
trifluoromethyl, trifluoromethoxy, nitro, cyano and hydroxy.
[0065] In a more preferred embodiment, R.sup.1 and R.sup.2,
independently of each other, represent a substituent selected from
the group consisting of halo, trifluoromethyl, trifluoromethoxy,
nitro, cyano and hydroxy.
[0066] In another more preferred embodiment, R.sup.1 and R.sup.2,
independently of each other, represent a substituent selected from
the group consisting of halo, trifluoromethyl, trifluoromethoxy,
nitro and cyano.
[0067] In a third more preferred embodiment, R.sup.1 and R.sup.2,
independently of each other, represent a substituent selected from
the group consisting of halo, and in particular fluoro, and
trifluoromethyl.
[0068] In a fourth more preferred embodiment, R.sup.1 represents
hydrogen or halo, and in particular fluoro; and R.sup.2 represents
trifluoromethyl, trifluoromethoxy, nitro or cyano.
[0069] In a fifth more preferred embodiment, R.sup.1 represents
halo, and in particular fluoro; and R.sup.2 represents
trifluoromethyl, trifluoromethoxy, nitro or cyano.
[0070] In a sixth more preferred embodiment, R.sup.1 represents
halo, and in particular fluoro; and R.sup.2 represents
trifluoromethyl.
[0071] In a sixth preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.3
represents amino or nitro.
[0072] In a more preferred embodiment, R.sup.3 represents
amino.
[0073] In another more preferred embodiment, R.sup.3 represents
nitro.
[0074] In a seventh preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 and
R.sup.5, independently of each other, represent hydrogen, halo,
trifluoromethyl, hydroxy, alkoxy, thioalkoxy, cycloalkoxy, alkyl,
cycloalkyl, sulfamoyl, piperidinyl, morpholinyl, or pyridinyl.
[0075] In a more preferred embodiment, R.sup.4 and R.sup.5,
independently of each other, represent hydrogen, hydroxy, alkoxy,
sulfamoyl or pyridinyl; or R.sup.4 and R.sup.5 together with the
phenyl ring to which they are attached form a bicyclic heterocyclic
ring selected from indolyl and indazolyl.
[0076] In another more preferred embodiment, R.sup.4 and R.sup.5,
independently of each other, represent hydrogen, halo,
trifluoromethyl, hydroxy, alkoxy, thioalkoxy, cycloalkoxy, alkyl,
cycloalkyl, sulfamoyl, piperidinyl, morpholinyl, or pyridinyl.
[0077] In a third more preferred embodiment, one of R.sup.4 and
R.sup.5 represents hydrogen; and the other of R.sup.4 and R.sup.5
represents hydroxy, halo, alkoxy, thioalkoxy, cycloalkoxy, alkyl,
cycloalkyl, sulfamoyl, piperidinyl, morpholinyl, or pyridinyl.
[0078] In a fourth more preferred embodiment, one of R.sup.4 and
R.sup.5 represents hydrogen; and the other of R.sup.4 and R.sup.5
represents hydroxy, alkoxy, sulfamoyl or pyridinyl.
[0079] In a fifth more preferred embodiment, one of R.sup.4 and
R.sup.5 represents hydrogen; and the other of R.sup.4 and R.sup.5
represents hydroxy.
[0080] In a sixth more preferred embodiment, one of R.sup.4 and
R.sup.5 represents hydrogen; and the other of R.sup.4 and R.sup.5
represents alkoxy, and in particular methoxy.
[0081] In a seventh more preferred embodiment, one of R.sup.4 and
R.sup.5 represents hydrogen; and the other of R.sup.4 and R.sup.5
represents sulfamoyl.
[0082] In an eight more preferred embodiment, one of R.sup.4 and
R.sup.5 represents hydrogen; and the other of R.sup.4 and R.sup.5
represents pyridinyl.
[0083] In a ninth more preferred embodiment, one of R.sup.4 and
R.sup.5 represents halo, and in particular fluoro or chloro, or
alkoxy, and in particular methoxy; and the other of R.sup.4 and
R.sup.5 represents halo, and in particular fluoro or chloro,
trifluoromethyl, alkoxy, and in particular methoxy.
[0084] In a tenth more preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula Ic or 1d, a stereoisomer thereof
or a mixture of its stereoisomers, or a pharmaceutically acceptable
salt thereof, wherein
[0085] R.sup.4 represents halo, trifluoromethyl, hydroxy, alkoxy,
cycloalkoxy, alkyl, sulfamoyl or pyridinyl.
[0086] In an eleventh more preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula Ic or 1d, a stereoisomer thereof
or a mixture of its stereoisomers, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 represents hydroxy, alkoxy, sulfamoyl
or pyridinyl.
[0087] In a twelfth more preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula Ic or 1d, a stereoisomer thereof
or a mixture of its stereoisomers, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 represents hydroxy.
[0088] In a thirteenth more preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula Ic or 1d, a stereoisomer thereof
or a mixture of its stereoisomers, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 represents alkoxy, and in particular
methoxy. p In a fourteenth more preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula Ic or 1d, a stereoisomer thereof
or a mixture of its stereoisomers, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 represents sulfamoyl.
[0089] In a fifteenth more preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula Ic or 1d, a stereoisomer thereof
or a mixture of its stereoisomers, or a pharmaceutically acceptable
salt thereof, wherein R.sup.4 represents pyridinyl, and in
particular pyridin-3-yl.
[0090] In an eight preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 and
R.sup.5 together with the phenyl ring to which they are attached
form a methylenedioxy group or ethylenedioxy group.
[0091] In a more preferred embodiment, R.sup.4 and R.sup.5 together
with the phenyl ring to which they are attached form a
methylenedioxy group.
[0092] In another more preferred embodiment, R.sup.4 and R.sup.5
together with the phenyl ring to which they are attached form a
ethylenedioxy group.
[0093] In a ninth preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 and
R.sup.5 together with the phenyl ring to which they are attached
form a bicyclic carbocyclic ring selected from naphthyl and
tetrahydronaphthalenyl.
[0094] In a more preferred embodiment, R.sup.4 and R.sup.5 together
with the phenyl ring to which they are attached form a naphthyl
ring.
[0095] In another more preferred embodiment, R.sup.4 and R.sup.5
together with the phenyl ring to which they are attached form a
tetrahydronaphthalenyl ring, and in particular a
5,6,7,8-tetrahydro-naphthalen-2-yl ring.
[0096] In a tenth preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is a compound of Formula I, Ia, Ib, Ic or Id, a
stereoisomer thereof or a mixture of its stereoisomers, or a
pharmaceutically acceptable salt thereof, wherein R.sup.4 and
R.sup.5 together with the phenyl ring to which they are attached
form a bicyclic heterocyclic ring selected from indolyl, indazolyl,
quinolinyl and isoquinolinyl.
[0097] In a more preferred embodiment, R.sup.4 and R.sup.5 together
with the phenyl ring to which they are attached form an indolyl
group, and in particular a 1H-indol-5-yl group.
[0098] In another more preferred embodiment, R.sup.4 and R.sup.5
together with the phenyl ring to which they are attached form an
indazolyl group, and in particular a1H-indazol-5-yl group.
[0099] In a third more preferred embodiment, R.sup.4 and R.sup.5
together with the phenyl ring to which they are attached form a
quinolinyl ring, and in particular a quinolin-8-yl ring.
[0100] In a fourth more preferred embodiment, R.sup.4 and R.sup.5
together with the phenyl ring to which they are attached form an
isoquinolinyl ring, and in particular an isoquinolin-5-yl ring.
[0101] In a most preferred embodiment, the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention is
[0102]
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(4-m-
ethoxy-phenyl)-amine;
[0103]
4-[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-ylamin-
o]-phenol;
[0104]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(4-methoxy-phenyl)-pyrim-
idine-4,5-diamine;
[0105]
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamin-
o]-phenol;
[0106]
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(6-m-
ethoxy-pyridin-3-yl)-amine;
[0107]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(6-methoxy-pyridin-3-yl)-
-pyrimidine-4,5-diamine;
[0108]
4-[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-ylamin-
o]-benzenesulfonamide;
[0109]
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamin-
o]-benzenesulfonamide;
[0110]
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(1H--
indol-5-yl)-amine;
[0111]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(1H-indol-5-yl)-pyrimidi-
ne-4,5-diamine;
[0112]
5-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamin-
o]-pyridin-2-ol;
[0113]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(1H-indazol-5-yl)-pyrimi-
dine-4,5-diamine;
[0114]
N*4*-Benzo[1,3]dioxol-5-yl-6-(2-fluoro-4-trifluoromethyl-phenyl)-py-
rimidine-4,5-diamine;
[0115]
N*4*-(4-Cyclopropylmethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-ph-
enyl)-pyrimidine-4,5-diamine;
[0116]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-naphthalen-1-yl-
-pyrimidine-4,5-diamine;
[0117]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(4-methoxy-phenyl)-2-met-
hyl-pyrimidine-4,5-diamine;
[0118]
N*4*-(2,4-Difluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2--
methyl-pyrimidine-4,5-diamine;
[0119]
N*4*-(4-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-meth-
yl-pyrimidine-4,5-diamine;
[0120]
N*4*-(2-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-meth-
yl-pyrimidine-4,5-diamine;
[0121]
N*4*-(2,4-Dichloro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2--
methyl-pyrimidine-4,5-diamine;
[0122]
N*4*-Benzo[1,3]dioxol-5-yl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2--
methyl-pyrimidine-4,5-diamine;
[0123]
N*4*-(3,5-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-
-methyl-pyrimidine-4,5-diamine;
[0124]
N*4*-(4-Chloro-3-trifluoromethyl-phenyl)-6-(2-fluoro-4-trifluoromet-
hyl-phenyl)-2-methyl-pyrimidine-4,5-diamine;
[0125]
N*4*-(3-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-meth-
yl-pyrimidine-4,5-diamine;
[0126]
N*4*-(4-Cyclohexyl-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2--
methyl-pyrimidine-4,5-diamine;
[0127]
N*4*-(4-Ethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-meth-
yl-pyrimidine-4,5-diamine;
[0128]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-p-tolyl-pyrimid-
ine-4,5-diamine;
[0129]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-isoquinolin-5-yl-2-methy-
l-pyrimidine-4,5-diamine;
[0130]
N*4*-(2,3-Dihydro-benzo[1,4]dioxin-6-yl)-6-(2-fluoro-4-trifluoromet-
hyl-phenyl)-2-methyl-pyrimidine-4,5-diamine;
[0131]
N*4*-(3,4-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-
-methyl-pyrimidine-4,5-diamine;
[0132]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(3-methoxy-phenyl)-2-met-
hyl-pyrimidine-4,5-diamine;
[0133]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-(3-methylsulfan-
yl-phenyl)-pyrimidine-4,5-diamine;
[0134]
N*4*-(2,4-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-
-methyl-pyrimidine-4,5-diamine;
[0135]
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-naphthalen-2-yl-
-pyrimidine-4,5-diamine;
[0136]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-5-nitro-
-pyrimidine;
[0137]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-pyrimid-
in-5-ylamine;
[0138] 4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrim id
in-4-yloxy]-phenol;
[0139]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-propyl-phenoxy)-
-pyrimidin-5-ylamine;
[0140]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-morpholin-4-yl--
phenoxy)-pyrimidin-5-ylamine;
[0141]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(quinolin-8-yloxy)-
-pyrimidin-5-ylamine;
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(5,6,7,8-tetrahydro-naph-
thalen-2-yloxy)-pyrimidin-5-ylamine;
[0142]
4-(4-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidin-5-ylamine;
[0143]
4-(Benzo[1,3]dioxol-5-yloxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)--
2-methyl-pyrimidin-5-ylamine;
[0144]
4-(2-Chloro-4-methoxy-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl-
)-2-methyl-pyrimidin-5-ylamine;
[0145]
4-(3-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidin-5-ylamine;
[0146]
4-(2-Chloro-4-trifluoromethyl-phenoxy)-6-(2-fluoro-4-trifluoromethy-
l-phenyl)-2-methyl-pyrimidin-5-ylamine;
[0147]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-2-methy-
l-pyrimidin-5-ylamine;
[0148]
4-(3-Chloro-5-methoxy-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl-
)-2-methyl-pyrimidin-5-ylamine;
[0149]
4-(3-tert-Butyl-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-me-
thyl-pyrimidin-5-ylamine;
[0150]
4-(4-tert-Butyl-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-me-
thyl-pyrimidin-5-ylamine;
[0151]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-piperidin-1-yl--
phenoxy)-pyrimidin-5-ylamine;
[0152]
4-(2-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidin-5-ylamine; or
[0153]
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-phenoxy-pyrimidin--
5-ylamine;
[0154] a stereoisomer thereof or a mixture of its stereoisomers, or
a pharmaceutically acceptable salt thereof.
[0155] Any combination of two or more of the embodiments described
herein is considered within the scope of the present invention.
Definition of Substituents
[0156] In the context of this invention halo represents fluoro,
chloro, bromo or iodo.
[0157] In the context of this invention an alkyl group designates a
univalent saturated, straight or branched hydrocarbon chain. The
hydrocarbon chain preferably contain of from one to eighteen carbon
atoms (C.sub.1-18-alkyl), more preferred of from one to six carbon
atoms (C.sub.1-6-alkyl; lower alkyl), including pentyl, isopentyl,
neopentyl, hexyl and isohexyl. In a preferred embodiment alkyl
represents a C.sub.1-4-alkyl group, including butyl, isobutyl,
secondary butyl, and tertiary butyl. In another preferred
embodiment of this invention alkyl represents a C.sub.1-3-alkyl
group, which may in particular be methyl, ethyl, propyl or
isopropyl.
[0158] In the context of this invention an alkoxy group designates
an "alkyl-O--" group, wherein alkyl designates a univalent
saturated, straight or branched hydrocarbon chain. The hydrocarbon
chain preferably contain of from one to eighteen carbon atoms
(C.sub.1-18-alkyl), more preferred of from one to six carbon atoms
(C.sub.1-6-alkyl; lower alkyl), including pentyl, isopentyl,
neopentyl, tertiary pentyl, hexyl and isohexyl. Preferred alkoxy
groups of the invention include methoxy, ethoxy and isopropoxy.
[0159] In the context of this invention an thioalkoxy group
designates an "alkyl-S-" group, wherein alkyl is as defined above.
Examples of preferred thioalkoxy groups of the invention include
methylthio (thiomethoxy or methylsulfanyl), and ethylthio
(thioethoxy or ethylsulfanyl).
[0160] In the context of this invention a cycloalkyl group
designates a cyclic alkyl group, preferably containing of from
three to seven carbon atoms (C.sub.3-7-cycloalkyl), including
cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl and
cycloheptyl.
[0161] In the context of this invention a cycloalkoxy group
designates a "cycloalkyl-O--" group, wherein cycloalkyl is as
defined above. A preferred alkoxy group of the invention is
cyclopropylmethoxy and cyclopropoxy.
Pharmaceutically Acceptable Salts
[0162] The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy)
derivative of the invention may be provided in any form suitable
for the intended administration. Suitable forms include
pharmaceutically (i.e. physiologically) acceptable salts, and pre-
or prodrug forms of the compound of the invention.
[0163] Examples of pharmaceutically acceptable addition salts
include, without limitation, the non-toxic inorganic and organic
acid addition salts such as the hydrochloride, the hydrobromide,
the nitrate, the perchlorate, the phosphate, the sulphate, the
formate, the acetate, the aconate, the ascorbate, the
benzenesulphonate, the benzoate, the cinnamate, the citrate, the
embonate, the enantate, the fumarate, the glutamate, the glycolate,
the lactate, the maleate, the malonate, the mandelate, the
methanesulphonate, the naphthalene-2-sulphonate derived, the
phthalate, the salicylate, the sorbate, the stearate, the
succinate, the tartrate, the toluene-p-sulphonate, and the like.
Such salts may be formed by procedures well known and described in
the art.
[0164] Metal salts of a 6-phenyl-pyrimidin-4-yl-(phenylamine or
phenoxy) derivative of the invention include alkali metal salts,
such as the sodium salt of a compound of the invention containing a
carboxy group.
Steric Isomers
[0165] It will be appreciated by those skilled in the art that the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivatives of the
present invention may exist in different stereo isomeric forms,
including enantiomers, diastereomers, as well as geometric isomers
(cis-trans isomers). The invention includes all such stereoisomers
and any mixtures thereof including racemic mixtures.
[0166] Racemic forms can be resolved into the optical antipodes by
known methods and techniques. One way of separating the
enantiomeric compounds (including enantiomeric intermediates)
is--in the case the compound being a chiral acid by use of an
optically active amine, and liberating the diastereomeric, resolved
salt by treatment with an acid. Another method for resolving
racemates into the optical antipodes is based upon chromatography
on an optical active matrix. Racemic compounds of the present
invention can thus be resolved into their optical antipodes, e.g.,
by fractional crystallisation of D- or L-(tartrates, mandelates, or
camphorsulphonate) salts for example.
[0167] Additional methods for the resolving the optical isomers are
known in the art. Such methods include those described by Jaques J,
Collet A, & Wilen S in "Enantiomers, Racemates, and
Resolutions", John Wiley and Sons, New York (1981).
[0168] Optical active compounds can also be prepared from optically
active starting materials or intermediates.
Methods of Producing 6-phenyl-pyrimidin-4-yl-(phenylamine or
phenoxy) Derivatives
[0169] The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy)
derivative of the invention may be prepared by conventional methods
for chemical synthesis, e.g. those described in the working
examples. The starting materials for the processes described in the
present application are known or may readily be prepared by
conventional methods from commercially available chemicals.
[0170] Also one compound of the invention can be converted to
another compound of the invention using conventional methods.
[0171] The end products of the reactions described herein may be
isolated by conventional techniques, e.g. by extraction,
crystallisation, distillation, chromatography, etc.
Biological Activity
[0172] The present invention is devoted to the provision novel
modulators of the nicotinic receptors, which modulators are useful
for the treatment of diseases or disorders related to the
cholinergic receptors, and in particular the nicotinic
acetylcholine receptor (nAChR). Preferred compounds of the
invention show a pronounced nicotinic acetylcholine .alpha.7
receptor subtype selectivity.
[0173] Due to their pharmacological profile the compounds of the
invention may be useful for the treatment of diseases or disorders
as diverse as those related to the cholinergic system of the
central nervous system (CNS), the peripheral nervous system (PNS),
diseases or disorders related to smooth muscle contraction,
endocrine diseases or disorders, diseases or disorders related to
neuro-degeneration, diseases or disorders related to inflammation,
pain, and withdrawal symptoms caused by the termination of abuse of
chemical substances.
[0174] The compounds of the invention may also be useful as
diagnostic tools or monitoring agents in various diagnostic
methods, and in particular for in vivo receptor imaging
(neuroimaging), and they may be used in labelled or unlabelled
form.
[0175] In a preferred embodiment, the disease, disorder or
condition contemplated according to the invention, and responsive
to modulation of nicotinic acetylcholine receptors is anxiety, a
cognitive disorder, a learning deficit, a memory deficit or
dysfunction, Alzheimer's disease, attention deficit, attention
deficit hyperactivity disorder, Parkinson's disease, Huntington's
disease, Amyotrophic Lateral Sclerosis, Gilles de la Tourette's
syndrome, depression, mania, manic depression, psychosis,
schizophrenia, obsessive compulsive disorders (OCD), panic
disorders, an eating disorder including anorexia nervosa, bulimia
and obesity, narcolepsy, nociception, AIDS-dementia, senile
dementia, peripheral neuropathy, autism, dyslexia, tardive
dyskinesia, hyperkinesia, epilepsy, post-traumatic syndrome, social
phobia, a sleeping disorder, pseudo dementia, Ganser's syndrome,
pre-menstrual syndrome, late luteal phase syndrome, chronic fatigue
syndrome, mutism, trichotillomania, jet-lag, hypertension, cardiac
arrhythmias, a smooth muscle contraction disorder including
convulsive disorders, angina pectoris, premature labour,
convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia,
hyperkinesia, premature ejaculation and erectile difficulty, an
endocrine system disorder including thyrotoxicosis and
pheochromocytoma, a neurodegenerative disorder, including transient
anoxia and induced neuro-degeneration, pain, mild, moderate or
severe pain, acute pain, chronic pain, pain of recurrent character,
neuropathic pain, pain caused by migraine, postoperative pain,
phantom limb pain, neuropathic pain, chronic headache, central
pain, pain related to diabetic neuropathy, to postherpetic
neuralgia or to peripheral nerve injury, an inflammatory disorder,
including an inflammatory skin disorder, acne, rosacea, Crohn's
disease, inflammatory bowel disease, ulcerative colitis and
diarrhoea, a disorder associated with withdrawal symptoms caused by
termination of use of addictive substances, including nicotine
withdrawal symptoms, opioid withdrawal symptoms including heroin,
cocaine and morphine, benzodiazepine withdrawal symptoms including
benzodiazepine-like drugs and alcohol.
[0176] In a more preferred embodiment, the disease, disorder or
condition responsive to modulation of nicotinic acetylcholine
receptors is a cognitive disorder, psychosis, schizophrenia or
depression.
[0177] In another more preferred embodiment, the disease, disorder
or condition responsive to modulation of nicotinic acetylcholine
receptors is associated with smooth muscle contractions, including
convulsive disorders, angina pectoris, premature labour,
convulsions, diarrhoea, asthma, epilepsy, tardive dyskinesia,
hyperkinesia, premature ejaculation and erectile difficulty.
[0178] In still another more preferred embodiment, the disease,
disorder or condition responsive to modulation of nicotinic
acetylcholine receptors is related to the endocrine system, such as
thyrotoxicosis and pheochromocytoma.
[0179] In yet another more preferred embodiment, the disease,
disorder or condition responsive to modulation of nicotinic
acetylcholine receptors is a neurodegenerative disorder including
transient anoxia and induced neuro-degeneration.
[0180] In a further more preferred embodiment, the disease,
disorder or condition responsive to modulation of nicotinic
acetylcholine receptors is pain, including mild, moderate or even
severe pain of acute, chronic or recurrent character, as well as
pain caused by migraine, postoperative pain, and phantom limb pain.
The pain may in particular be neuropathic pain, chronic headache,
central pain, pain related to diabetic neuropathy, to postherpetic
neuralgia, or to peripheral nerve injury.
[0181] In a further more preferred embodiment, the disease,
disorder or condition responsive to modulation of nicotinic
acetylcholine receptors is an inflammatory skin disorder such as
acne and rosacea, Crohn's disease, inflammatory bowel disease,
ulcerative colitis, and diarrhoea.
[0182] Finally the compounds of the invention may be useful for the
treatment of withdrawal symptoms caused by termination of use of
addictive substances. Such addictive substances include nicotine
containing products such as tobacco, opioids such as heroin,
cocaine and morphine, benzodiazepines and benzodiazepine-like
drugs, and alcohol. Withdrawal from addictive substances is in
general a traumatic experience characterised by anxiety and
frustration, anger, anxiety, difficulties in concentrating,
restlessness, decreased heart rate and increased appetite and
weight gain.
[0183] In this context "treatment" covers treatment, prevention,
prophylactics and alleviation of withdrawal symptoms and abstinence
as well as treatment resulting in a voluntary diminished intake of
the addictive substance.
Pharmaceutical Compositions
[0184] In another aspect the invention provides novel
pharmaceutical compositions comprising a therapeutically effective
amount of 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy)
derivative of the invention.
[0185] While a 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy)
derivative of the invention for use in therapy may be administered
in the form of the raw compound, it is preferred to introduce the
active ingredient, optionally in the form of a physiologically
acceptable salt, in a pharmaceutical composition together with one
or more adjuvants, excipients, carriers, buffers, diluents, and/or
other customary pharmaceutical auxiliaries.
[0186] In a preferred embodiment, the invention provides
pharmaceutical compositions comprising the
6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy) derivative of the
invention, or a pharmaceutically acceptable salt or derivative
thereof, together with one or more pharmaceutically acceptable
carriers therefore, and, optionally, other therapeutic and/or
prophylactic ingredients know and used in the art. The carrier(s)
must be "acceptable" in the sense of being compatible with the
other ingredients of the formulation and not harmful to the
recipient thereof.
[0187] The pharmaceutical composition of the invention may be
administered by any convenient route, which suits the desired
therapy. Preferred routes of administration include oral
administration, in particular in tablet, in capsule, in drage, in
powder, or in liquid form, and parenteral administration, in
particular cutaneous, subcutaneous, intramuscular, or intravenous
injection. The pharmaceutical composition of the invention can be
manufactured by the skilled person by use of standard methods and
conventional techniques appropriate to the desired formulation.
When desired, compositions adapted to give sustained release of the
active ingredient may be employed.
[0188] Further details on techniques for formulation and
administration may be found in the latest edition of Remington's
Pharmaceutical Sciences (Maack Publishing Co., Easton, Pa.).
[0189] The actual dosage depends on the nature and severity of the
disease being treated, and is within the discretion of the
physician, and may be varied by titration of the dosage to the
particular circumstances of this invention to produce the desired
therapeutic effect. However, it is presently contemplated that
pharmaceutical compositions containing of from about 0.1 to about
500 mg of active ingredient per individual dose, preferably of from
about 1 to about 100 mg, most preferred of from about 1 to about 10
mg, are suitable for therapeutic treatments.
[0190] The active ingredient may be administered in one or several
doses per day. A satisfactory result can, in certain instances, be
obtained at a dosage as low as 0.1 .mu.g/kg i.v. and 1 .mu.g/kg
p.o. The upper limit of the dosage range is presently considered to
be about 10 mg/kg i.v. and 100 mg/kg p.o. Preferred ranges are from
about 0.1 .mu.g/kg to about 10 mg/kg/day i.v., and from about 1
.mu.g/kg to about 100 mg/kg/day p.o.
Methods of Therapy
[0191] The 6-phenyl-pyrimidin-4-yl-(phenylamine or phenoxy)
derivatives of the present invention are valuable nicotinic
receptor modulators, and therefore useful for the treatment of a
range of ailments involving cholinergic dysfunction as well as a
range of disorders responsive to the action of nAChR
modulators.
[0192] In another aspect the invention provides a method for the
treatment, prevention or alleviation of a disease or a disorder or
a condition of a living animal body, including a human, which
disease, disorder or condition is responsive to modulation of
cholinergic receptors, and which method comprises administering to
such a living animal body, including a human, in need thereof an
effective amount of a 6-phenyl-pyrimidin-4-yl-(phenylamine or
phenoxy) derivative of the invention.
[0193] In the context of this invention the term "treatment" covers
treatment, prevention, prophylaxis or alleviation, and the term
"disease" covers illnesses, diseases, disorders and conditions
related to the disease in question.
[0194] The preferred indications contemplated according to the
invention are those stated above.
[0195] It is at present contemplated that suitable dosage ranges
are 0.1 to 1000 milligrams daily, 10-500 milligrams daily, and
especially 30-100 milligrams daily, dependent as usual upon the
exact mode of administration, form in which administered, the
indication toward which the administration is directed, the subject
involved and the body weight of the subject involved, and further
the preference and experience of the physician or veterinarian in
charge.
[0196] A satisfactory result can, in certain instances, be obtained
at a dosage as low as 0.005 mg/kg i.v. and 0.01 mg/kg p.o. The
upper limit of the dosage range is about 10 mg/kg i.v. and 100
mg/kg p.o. Preferred ranges are from about 0.001 to about 1 mg/kg
i.v. and from about 0.1 to about 10 mg/kg p.o.
EXAMPLES
[0197] The invention is further illustrated with reference to the
following examples, which are not intended to be in any way
limiting to the scope of the invention as claimed.
Example 1
Preparatory Example
General Synthetic Procedure for the Compounds of the Invention
[0198] Nucleophilic substitution of a commercial
4,6-dihalo-5-nitropyrimidine with the appropriate commercial
aniline in boiling 2-propanol yielded the correspondent
phenyl-pyrimidin-4-yl-amines (A), as previously described by Clark,
R. L. et al. in Journal of Medicinal Chemistry 21(9), 965-965,
1978. Suzuki coupling reaction of these latter compounds with the
suitably-substituted benzeneboronic acids afforded the
(6-phenyl-5-nitro-pyrimidin-4-yl)-phenyl-amines (B), as suggested
by Hauser D R J et al. in Journal of Medicinal Chemistry 2007 50
(9) 2060-2066. These latter were catalytically hydrogenated to give
the correspondent (6-phenyl-5-amino-pyrim id in-4-yl)-phenyl-am
ines (C). Those (6-phenyl-5-nitro-pyrimidin-4-yl)-phenyl-amines (B)
and (6-phenyl-5-amino-pyrimidin-4-yl)-phenyl-amines (C) bearing a
methoxy substituent (R3) were subjected to ether hydrolysis upon
mild nucleophilic substitution with the Lewis acid boron
tribromide, to afford the
(6-phenyl-5-amino-pyrimidin-4-yl)-phenyl-amines (D).
##STR00008##
Experimental Procedures
Intermediates
(6-Chloro-5-nitro-pvrimidin-4-yl)-(4-methoxy-phenyl)-amine
(INT-1)
[0199] To a stirred and ice-cooled solution of
4,6-dichloro-5-nitropyrimidine (1.000 g, 5.1553 mmol, 1 eq) in
anhydrous 2-propanol (10 ml), 4-methoxy-phenylamine (0.6984 g,
5.6708 mmol, 1.1 eq) and triethylamine (1.304 g, 12.888 mmol, 2.5
eq) were added drop-wise and the mixture refluxed under a nitrogen
atmosphere for 2 hours. The resulting reaction mixture was
evaporated, and the solid residue was suspended in water (100 ml)
and extracted with chloroform (150 ml.times.3). The combined
organic layers were washed with brine, dried over anhydrous sodium
sulphate, filtered and evaporated, to afford the title compound
(1.400 g, 96% mass balance) as a red solid. This latter was
purified by column chromatography over silica gel eluting with 5%
ethyl acetate in hexane (0.600 g, 41% yield; MH+ 281, 96% pure at
LCMS).
(6-Chloro-5-nitro-pyrimidin-4-yl)-(6-methoxy-pyridin-3-yl)-amine
(INT-2)
[0200] To a stirred and ice-cooled solution of
4,6-dichloro-5-nitropyrimidine (2.000 g, 10.3105 mmol, 1 eq) in
anhydrous 2-propanol (40 ml), 6-methoxy-pyridin-3-ylamine (1.408 g,
11.3416 mmol, 1.1 eq) and triethylamine (2.608 g, 25.7762 mmol, 2.5
eq) were added drop-wise and the mixture refluxed under a nitrogen
atmosphere for 2 hours. The resulting reaction mixture was
evaporated, and the solid residue was suspended in water (150 ml)
and extracted with ethyl acetate (200 ml.times.3). The combined
organic layers were washed with brine, dried over anhydrous sodium
sulphate, filtered and evaporated, to afford the title compound
(2.600 g, 96% mass balance) as a yellow solid. This latter was
purified by column chromatography over silica gel eluting with 7%
ethyl acetate in hexane (3.200 g, 74% yield; MH+ 282, 98% pure at
LCMS).
4-(6-Chloro-5-nitro-pyrimidin-4-ylamino)-benzenesulfonamide
(INT-3)
[0201] To a stirred and ice-cooled solution of
4,6-dichloro-5-nitropyrimidine (3.000 g, 15.4658 mmol, 1 eq) in
anhydrous 2-propanol (30 ml), 4-amino-benzenesulfonamide (2.718 g,
15.4658 mmol, 1.1 eq) and triethylamine (3.130 g, 30.9316 mmol, 2
eq) were added drop-wise and the mixture refluxed under a nitrogen
atmosphere for 3 hours. The resulting reaction mixture was
evaporated, and the solid residue was suspended in water (150 ml)
and extracted with ethyl acetate (200 ml.times.3). The combined
organic layers were washed with brine, dried over anhydrous sodium
sulphate, filtered and evaporated, to afford the title compound
(4.500 g, 89% mass balance) as a yellow solid. This latter was
purified by column chromatography over silica gel eluting with 15%
ethyl acetate in hexane (1.400 g, 27% yield; MH+ 330, 93% pure at
LCMS).
(6-Chloro-5-nitro-pyrimidin-4-yl)-(1H-indol-5-yl)-amine (INT-4)
[0202] To a stirred and ice-cooled solution of
4,6-dichloro-5-nitropyrimidine (2.000 g, 10.3105 mmol, 1 eq) in
anhydrous 2-propanol (20 ml), 1H-Indol-5-ylamine (1.363 g, 10.3105
mmol, 1 eq) and triethylamine (2.0866 g, 20.621 mmol, 2 eq) were
added drop-wise and the mixture refluxed under a nitrogen
atmosphere for 2 hours. The resulting reaction mixture was
evaporated, and the solid residue was suspended in water (100 ml)
and extracted with ethyl acetate (120 ml.times.3). The combined
organic layers were washed with brine, dried over anhydrous sodium
sulphate, filtered and evaporated, to afford the title compound
(2.900 g, 97% mass balance) as a red solid. This latter was
purified by column chromatography over silica gel eluting with 12%
ethyl acetate in hexane (0.651 g, 21% yield; MH+ 289, 99% pure at
LCMS).
Compounds of the Invention
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(4-methoxy--
phenyl)-amine (Compound 1.1)
[0203] A mixture of
(6-chloro-5-nitro-pyrimidin-4-yl)-(4-methoxy-phenyl)-amine (INT-1;
0.500 g, 1.7815 mmol, 1 eq),
2-fluoro-4-(trifluoromethyl)phenylboronic acid (0.4075 g, 1.9597
mmol, 1.1 eq), sodium carbonate (0.3776 g, 3.563 mmol, 2 eq) and
1,4-dioxane (10 ml) was degassed with nitrogen and kept under a
nitrogen atmosphere during the entire course of the reaction. To
the degassed mixture, palladium (II)
(bistriphenylphosphine)dichloride (0.0625 g, 0.0891 mmol, 0.05 eq)
was added and the resulting reaction mixture, refluxed overnight
and cooled to room temperature, was worked up by evaporation to
dryness followed by addition of water and finally extracted with
chloroform. The combined organic layers, dried over anhydrous
MgSO4, afforded upon evaporation a red solid material (0.600 g),
which eluted over silica gel (60-120 mesh) with 7% ethyl acetate in
hexane gave 0.220 g (30% yield) of the pure title compound as an
orange solid. M.p. 155.6-155.8.degree. C. LC-ESI-HRMS of [M+H]+
shows 409.0904 Da. Calc. 409.092378 Da, dev. -4.8 ppm.
4-[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-ylamino]-phen-
ol (Compound 1.2)
[0204] To a solution of
[6-(2-fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(4-methoxy-
-phenyl)-amine (Compound 1; 0.400 g, 0.9796 mmol, 1 eq) in
anhydrous dichloromethane (10 ml), cooled to -78.degree. C. and
kept under nitrogen, a solution of boron tribromide (0.9816 g,
.about.0.37 ml, 5.7799 mmol, 4 eq) in anhydrous dichloromethane (5
ml) was added drop-wise. The reaction mixture was allowed to attain
room temperature spontaneously and stirred overnight. The mixture
was then cooled again in an ice-salt bath and the excess of the
reagent was decomposed by treatment with methanol (10 ml) followed
by water (15 ml) and finally extracted with chloroform. The
combined organic layers, dried over anhydrous MgSO.sub.4, afforded
upon evaporation a black solid material (0.350 g), which eluted
over silica gel (60-120 mesh) with 11% ethyl acetate in hexane gave
0.166 g (42% yield) of the pure (>99% at HPLC) title compound as
a brown solid. M.p. 169-171.5.degree. C. LC-ESI-HRMS of [M+H]+
shows 395.0754 Da. Calc. 395.076728 Da, dev. -3.4 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(4-methoxy-Phenyl)-pyrimidine-4-
,5-diamine (Compound 1.3)
[0205] A degassed mixture of a solution of
[6-(2-fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(4-methoxy-
-phenyl)-amine (Compound 1; 1.000 g, 2.4491 mmol, 1 eq) in methanol
(10 ml) and raney-nickel (0.100 g, .about.0.3 eq) was put under a
hydrogen atmosphere and stirred at room temperature for 4 hours.
The resulting reaction mixture was filtered through a celite bed,
washed with methanol (50 ml.times.3) and the filtrate evaporated
under reduced pressure to furnish a solid residue. This material
was dissolved in chloroform and the organic layer, washed with
water and dried over anhydrous MgSO.sub.4, afforded upon
evaporation 0.800 g (86% yield) of the title compound as a white
solid, which is 99% pure at HPLC. M.p. 212,1-213.2.degree. C.
LC-ESI-HRMS of [M+H]+ shows 379.1172 Da. Calc. 379.118198 Da, dev.
-2.6 ppm.
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-phen-
ol (Compound 1.4)
[0206] To a solution of
6-(2-fluoro-4-trifluoromethyl-phenyl)-N*4*-(4-methoxy-phenyl)-pyrimidine--
4,5-diamine (Compound 3; 1.300 g, 3.4362 mmol, 1 eq) in anhydrous
dichloromethane (15 ml), cooled to -78.degree. C. and kept under
nitrogen, a solution of boron tribromide (6.026 g, .about.2.3 ml,
24.0534 mmol, 7 eq) in anhydrous dichloromethane (10 ml) was added
drop-wise. The reaction mixture was allowed to attain room
temperature spontaneously and stirred overnight. The mixture was
then cooled again in an ice-salt bath and the excess of the reagent
was decomposed by treatment with methanol (20 ml) followed by water
(25 ml) and finally extracted with chloroform. The combined organic
layers, dried over anhydrous MgSO.sub.4, afforded upon evaporation
a white solid material (.about.1.100 g), which eluted over silica
gel (230-400 mesh) with 30% ethyl acetate in hexane gave 0.850 g
(70% yield) of the pure (>99% at HPLC) title compound as an
off-white solid. M.p. 194.2-195.7.degree. C. LC-ESI-HRMS of [M+H]+
shows 365.1026 Da. Calc. 30 365.102548 Da, dev. 0.1 ppm.
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(6-methoxy--
pyridin-3-yl)-amine (Compound 1.5)
[0207] To a degassed mixture of
(6-chloro-5-nitro-pyrimidin-4-yl)-(6-methoxy-pyridin-3-yl)-amine
(INT-2; 2.700 g, 9.5861 mmol, 1 eq),
2-fluoro-4-(trifluoromethyl)phenylboronic acid (2.192 g, 10.5447
mmol, 1.1 eq), sodium carbonate (2.540 g, 23.9652 mmol, 2.5 eq),
1,4-dioxane (40 ml) and water (20 ml), palladium (II)
(bistriphenylphosphine)dichloride (0.3364 g, 0.4793 mmol, 0.05 eq)
was added and the resulting reaction mixture, refluxed for 5 hours
and cooled to room temperature, was worked up by concentration
under reduced pressure followed by addition of water and finally
extracted with chloroform. The combined organic layers, dried over
anhydrous MgSO4, afforded upon evaporation a brown gummy material
(3.200 g, 82% mass balance), which eluted over silica gel (60-120
mesh) with 7% ethyl acetate in hexane gave 1.700 g (36% yield) of
the pure title compound as an orange solid. MH+ 410.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(6-methoxy-rwrid
in-3-yl)-pyrimidine-4,5-diamine (Compound 1.6)
[0208] A degassed mixture of a solution of
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(6-methoxy-
-pyridin-3-yl)-amine (Compound 4; 1.000 g, 2.4432 mmol, 1 eq) in
methanol (30 ml) and raney-nickel (0.100 g, .about.0.3 eq) was put
under a hydrogen atmosphere and stirred at room temperature
overnight. The resulting reaction mixture was filtered through a
celite bed, washed with methanol (50 ml.times.3) and the filtrate
evaporated under reduced pressure to furnish a solid residue. This
material was dissolved in chloroform and the organic layer, washed
with water and dried over anhydrous MgSO.sub.4, afforded upon
evaporation 0.700 g (77% yield) of the title compound as a white
solid, which is 96% pure at HPLC. M.p. 188.6-189.9.degree. C.
4-[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-ylamino]-benz-
enesulfonamide (Compound 1.7)
[0209] To a degassed mixture of
4-(6-chloro-5-nitro-pyrimidin-4-ylamino)-benzenesulfonamide (INT-3;
1.400 g, 4.246 mmol, 1 eq),
2-fluoro-4-(trifluoromethyl)phenylboronic acid (0.9711 g, 4.6706
mmol, 1.1 eq), sodium carbonate (1.125 g, 10.615 mmol, 2.5 eq),
1,4-dioxane (15 ml) and water (5 ml), palladium (II)
(bistriphenylphosphine)dichloride (0.149 g, 0.2123 mmol, 0.05 eq)
was added and the resulting reaction mixture, refluxed for 5 hours
and cooled to room temperature, was worked up by concentration
under reduced pressure followed by addition of water and finally
extracted with chloroform. The combined organic layers, dried over
anhydrous MgSO4, afforded upon evaporation a yellow solid material
(1.700 g, 87% mass balance), which eluted over silica gel (230-400
mesh) with 12% ethyl acetate in hexane gave 0.503 g (32% yield) of
the pure title compound as an orange solid. MH+ 458.
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-benz-
enesulfonamide (Compound 1.8)
[0210] A degassed mixture of a solution of
4-[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-ylamino]-ben-
zenesulfonamide (Compound 6; 0.900 g, 1.9678 mmol, 1 eq) in
methanol (15 ml) and raney-nickel (0.080 g, .about.0.3 eq) was put
under a hydrogen atmosphere and stirred at room temperature
overnight. The resulting reaction mixture was filtered through a
celite bed, washed with methanol (50 ml.times.3) and the filtrate
evaporated under reduced pressure to furnish a solid residue. This
material was dissolved in chloroform and the organic layer, washed
with water and dried over anhydrous MgSO.sub.4, afforded upon
evaporation 0.700 g (77% yield) of the title compound as a white
solid. After washing with diethylether, the residual solid (0.402
g, 41% yield) resulted to be 96% pure at HPLC.
[6-(2-Fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(1H-indol-5-
-yl)-amine (Compound 1.9)
[0211] To a degassed mixture of
(6-chloro-5-nitro-pyrimidin-4-yl)-(1H-indol-5-yl)-amine (INT-4;
1.200 g, 4.1425 mmol, 1 eq),
2-fluoro-4-(trifluoromethyl)phenylboronic acid (0.9474 g, 4.5568
mmol, 1.1 eq), sodium carbonate (1.0976 g, 10.3562 mmol, 2.5 eq),
1,4-dioxane (10 ml) and water (5 ml), palladium (II)
(bistriphenylphosphine)dichloride (0.1454 g, 0.2071 mmol, 0.05 eq)
was added and the resulting reaction mixture, refluxed for 5 hours
and cooled to room temperature, was worked up by concentration
under reduced pressure followed by addition of water and finally
extracted with chloroform. The combined organic layers, dried over
anhydrous MgSO4, afforded upon evaporation a yellow solid material
(1.600 g, 94% mass balance), which eluted over silica gel (230-400
mesh) with 10% ethyl acetate in hexane gave 0.633 g (37% yield) of
the pure title compound as a red solid. M.p. 147.4-148.9.degree.
C.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(1H-indol-5-yl)-pyrimidine-4,5--
diamine (Compound 1.10)
[0212] A degassed mixture of a solution of
[6-(2-fluoro-4-trifluoromethyl-phenyl)-5-nitro-pyrimidin-4-yl]-(1H-indol--
5-yl)-amine (Compound 8; 0.500 g, 1.1981 mmol, 1 eq) in methanol
(15 ml) and raney-nickel (0.049 g, .about.0.3 eq) was put under a
hydrogen atmosphere and stirred at room temperature overnight. The
resulting reaction mixture was filtered through a celite bed,
washed with methanol (50 ml.times.3) and the filtrate evaporated
under reduced pressure to furnish a solid residue. This material
was dissolved in chloroform and the organic layer, washed with
water and dried over anhydrous MgSO.sub.4, afforded upon
evaporation 0.450 g (97% yield) of the title compound as a white
solid. After washing with chloroform, the residual solid (0.241 g,
51% yield) resulted to be 96% pure at HPLC. MH+ 387.
[0213] In analogy with the procedure described above the following
compounds were made.
5-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-ylamino]-pyri-
din-2-ol (Compound 1.11)
[0214] LC-ESI-HRMS of [M+H]+ shows 366.0957454 Da. Calc. 366.097252
Da, dev. -4.1 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(1H-indazol-5-yl)-pyrimidine-4,-
5-diamine (Compound 1.12)
[0215] LC-ESI-HRMS of [M+H]+ shows 389.1131 Da. Calc. 389.113236
Da, dev. -0.3 ppm.
N*4*-Benzo[1,3]dioxol-5-yl-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-
e-4,5-diamine (Compound 1.13)
[0216] LC-ESI-HRMS of [M+H]+ shows 393.098728111807 Da. Calc.
393.096918 Da, dev. 4.6 ppm.
N*4*-(4-Cyclopropylmethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-p-
yrimidine-4,5-diamine (Compound 1.14)
[0217] LC-ESI-HRMS of [M+H]+ shows 419.1494 Da. Calc. 419.148953
Da, dev. 1.1 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-naphthalen-1-yl-pyrimi-
dine-4,5-diamine (Compound 1.15)
[0218] LC-ESI-HRMS of [M+H]+ shows 413.13845 Da. Calc. 413.138388
Da, dev. 0.2 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(4-methoxy-phenyl)-2-methyl-pyr-
imidine-4,5-diamine (Compound 1.16)
[0219] LC-ESI-HRMS of [M+H]+ shows 393.13371 Da. Calc. 393.133303
Da, dev. 1 ppm.
N*4*-(2,4-Difluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl--
pyrimidine-4,5-diamine (Compound 1.17)
[0220] LC-ESI-HRMS of [M+H]+ shows 399.10395 Da. Calc. 399.103894
Da, dev. 0.1 ppm.
N*4*-(4-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyri-
midine-4,5-diamine (Compound 1.18)
[0221] LC-ESI-HRMS of [M+H]+ shows 381.11384 Da. Calc. 381.113316
Da, dev. 1.4 ppm.
N*4*-(2-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyri-
midine-4,5-diamine (Compound 1.19)
[0222] LC-ESI-HRMS of [M+H]+ shows 381.11388 Da. Calc. 381.113316
Da, dev. 1.5 ppm.
N*4*-(2,4-Dichloro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl--
pyrimidine-4,5-diamine (Compound 1.20)
[0223] LC-ESI-HRMS of [M+H]+ shows 431.04512 Da. Calc. 431.044794
Da, dev. 0.8 ppm.
N*4*-Benzo[1,3]dioxol-5-yl-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl--
pyrimidine-4,5-diamine (Compound 1.21)
[0224] LC-ESI-HRMS of [M+H]+ shows 407.11266 Da. Calc. 407.112568
Da, dev. 0.2 ppm.
N*4*-(3,5-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidine-4,5-diamine (Compound 1.22)
[0225] LC-ESI-HRMS of [M+H]+ shows 423.14385 Da. Calc. 423.143868
Da, dev. 0 ppm.
N*4*-(4-Chloro-3-trifluoromethyl-phenyl)-6-(2-fluoro-4-trifluoromethyl-phe-
nyl)-2-methyl-pyrimidine-4,5-diamine (Compound 1.23)
[0226] LC-ESI-HRMS of [M+H]+ shows 465.07081 Da. Calc. 465.07115
Da, dev. -0.7 ppm.
N*4*-(3-Fluoro-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyri-
midine-4,5-diamine (Compound 1.24)
[0227] LC-ESI-HRMS of [M+H]+ shows 381.11375 Da. Calc. 381.113316
Da, dev. 1.1 ppm.
N*4*-(4-Cyclohexyl-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl--
pyrimidine-4,5-diamine (Compound 1.25)
[0228] LC-ESI-HRMS of [M+H]+ shows 445.20112 Da. Calc. 445.200988
Da, dev. 0.3 ppm.
N*4*-(4-Ethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyri-
midine-4,5-diamine (Compound 1.26)
[0229] LC-ESI-HRMS of [M+H]+ shows 407.14925 Da. Calc. 407.148953
Da, dev. 0.7 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-p-tolyl-pyrimidine-4,5-
-diamine (Compound 1.27)
[0230] LC-ESI-HRMS of [M+H]+ shows 377.13879 Da. Calc. 377.138388
Da, dev. 1.1 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-isoquinolin-5-yl-2-methyl-pyrim-
idine-4,5-diamine (Compound 1.28)
N*4*-(2,3-Dihydro-benzo[1,4
dioxin-6-yl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrimidine-4,-
5-diamine (Compound 1.29)
[0231] LC-ESI-HRMS of [M+H]+ shows 421.12824 Da. Calc. 421.128218
Da, dev. 0 ppm.
N*4*-(3,4-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidine-4,5-diamine (Compound 1.30)
[0232] LC-ESI-HRMS of [M+H]+ shows 423.14401 Da. Calc. 423.143868
Da, dev. 0.3 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-N*4*-(3-methoxy-phenyl)-2-methyl-pyr-
imidine-4,5-diamine (Compound 1.31)
[0233] LC-ESI-HRMS of [M+H]+ shows 393.13367 Da. Calc. 393.133303
Da, dev. 0.9 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-(3-methylsulfanyl-phen-
yl)-pyrimidine-4,5-diamine (Compound 1.32)
[0234] LC-ESI-HRMS of [M+H]+ shows 409.11069 Da. Calc. 409.110459
Da, dev. 0.6 ppm.
N*4*-(2,4-Dimethoxy-phenyl)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-
-pyrimidine-4,5-diamine (Compound 1.33)
[0235] LC-ESI-HRMS of [M+H]+ shows 423.14369 Da. Calc. 423.143868
Da, dev. -0.4 ppm.
6-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-N*4*-naphthalen-2-v1-pyrimi-
dine-4,5-diamine (Compound 1.34)
[0236] LC-ESI-HRMS of [M+H]+ shows 413.13855 Da. Calc. 413.138388
Da, dev. 0.4 ppm.
Example 2
Preparatory Example
##STR00009##
[0237] 4-Chloro-6-(4-methoxy-phenoxy)-5-nitro-pyrimidine
(Intermediate compound A)
[0238] To a stirred and ice-cooled solution of
4,6-dichloro-5-nitropyrimidine (3.000 g, 15.4658 mmol, 1 eq) in
anhydrous 2-propanol (30 ml), 4-methoxyphenol (2.112 g, 17.0124
mmol, 1.1 eq) and triethylamine (3.913 g, 38.6645 mmol, 2.5 eq)
were added drop-wise and the mixture stirred at room temperature
under a nitrogen atmosphere for 2 hours. The resulting reaction
mixture was evaporated, and the solid residue was suspended in
water and extracted with ethyl acetate. The combined organic layers
were washed with brine, dried over anhydrous sodium sulphate,
filtered and evaporated, to afford the title compound (4.120 g,
100% mass balance) as a yellow solid. This latter was purified by
column chromatography over silica gel eluting with 6-10% ethyl
acetate in petroleum ether (2.801g, 61% yield; MH+ 282, >97%
pure at LCMS).
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-5-nitro-pyrimi-
dine (Compound 2.1)
[0239] A mixture of
4-chloro-6-(4-methoxy-phenoxy)-5-nitro-pyrimidine (Compound A;
2.300 g, 8.166 mmol, 1 eq),
2-fluoro-4-(trifluoromethyl)phenylboronic acid (1.868 g, 8.9826
mmol, 1.1 eq), sodium carbonate (1.731 g, 16.332 mmol, 2 eq), 1,2
dimethoxyethane (15 ml) and water (7 ml) was degassed with nitrogen
and kept under a nitrogen atmosphere during the entire course of
the reaction. To the degassed mixture, palladium (II)
(bistriphenylphosphine)dichloride (0.287 g, 0.4083 mmol, 0.05 eq)
was added and the resulting reaction mixture, refluxed for 2 hours
and cooled to room temperature, was worked up by evaporation to
dryness followed by addition of water and finally extracted with
ethyl acetate. The combined organic layers, dried over anhydrous
MgSO4, afforded upon evaporation a brown gummy material
(.about.3.35 g), which eluted over silica gel (230-400 mesh) with
10% ethyl acetate in petroleum ether gave 0.965 g (.about.30%
yield) of the pure title compound as an off-white solid.
[0240] M.p. 203.8.degree. C.-205.2.degree. C. LC-ESI-HRMS of [M+H]+
shows 410.0764 Da. Calc. 410.075849 Da, dev. 1.3 ppm.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-pyrimidin-5-yl-
amine (Compound 2.2)
[0241] A degassed mixture of a solution of
4-(2-fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-5-nitro-pyrim-
idine (Compound 11; 1.500 g, 3.6648 mmol, 1 eq) in methanol (50 ml)
and raney-nickel (0.150 g, .about.0.3 eq) was put under a hydrogen
atmosphere and stirred at room temperature for 3 hours. The
resulting reaction mixture was filtered through a celite bed,
washed with methanol and the filtrate evaporated under reduced
pressure to furnish a solid residue (.about.1.35 g). This latter
material was purified by elution over neutral alumina with 10%
ethyl acetate in petroleum, to obtain 0.850 g (61% yield) of the
title compound as a white solid.
[0242] M.p. 129.0.degree.C.-130.4.degree. C. LC-ESI-HRMS of [M+H]+
shows 380.1027 Da. Calc. 380.101669 Da, dev. 2.7 ppm.
4-[5-Amino-6-(2-fluoro-4-trifluoromethyl-phenyl)-pyrimidin-4-yloxyl-phenol
(Compound 2.3)
[0243] To a solution of
[4-(2-fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-pyrimidin-5--
ylamine (Compound 12; 0.500 g, 1.3182 mmol, 1 eq) in anhydrous
dichloromethane (20 ml), cooled to -78.degree. C. and kept under
nitrogen, a solution of boron tribromide (2.312 g, .about.0.87 ml,
9.2274 mmol, 7 eq) in anhydrous dichloromethane (5 ml) was added
drop-wise. The reaction mixture was allowed to attain room
temperature spontaneously and stirred overnight. The mixture was
then cooled again in an ice-salt bath and the excess of the reagent
was decomposed by treatment with methanol (10 ml) followed by water
(15 ml) and finally extracted with chloroform. The combined organic
layers, dried over anhydrous MgSO.sub.4, afforded upon evaporation
a yellow solid material (.about.0.45 g), which eluted over neutral
alumina with 25% ethyl acetate in petroleum ether gave 0.330 g (68%
yield) of the pure title compound as a white solid.
[0244] M.p. 212.2.degree. C.-213.5.degree. C. LC-ESI-HRMS of [M+H]+
shows 366.0855 Da. Calc. 366.086019 Da, dev. -1.4 ppm.
[0245] In analogy with the procedure described above the following
compounds were made.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-propyl-phenoxy)-Pyrimi-
din-5-ylamine (Compound 2.4)
[0246] LC-ESI-HRMS of [M+H]+ shows 406.15429 Da. Calc. 406.153704
Da, dev. 1.4 ppm.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-morpholin-4-yl-phenoxy-
)-pyrimidin-5-ylamine (Compound 2.5)
[0247] LC-ESI-HRMS of [M+H]+ shows 449.1593 Da. Calc. 449.159518
Da, dev. -0.5 ppm.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(quinolin-8-yloxy)-Pyrimi-
din-5-ylamine (Compound 2.6)
[0248] LC-ESI-HRMS of [M+H]+ shows 415.11798 Da. Calc. 415.117653
Da, dev. 0.8 ppm.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(5,6,7,8-tetrahydro-napht-
halen-2-yloxy)-Pyrimidin-5-ylamine (Compound 2.7)
[0249] LC-ESI-HRMS of [M+H]+ shows 418.15389 Da. Calc. 418.153704
Da, dev. 0.4 ppm.
4-(4-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrimi-
din-5-ylamine (Compound 2.8)
[0250] LC-ESI-HRMS of [M+H]+ shows 382.09756 Da. Calc. 382.097332
Da, dev. 0.6 ppm.
4-(Benzo[1,3
dioxol-5-yloxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrimidin--
5-ylamine (Compound 2.9)
[0251] LC-ESI-HRMS of [M+H]+ shows 408.09633 Da. Calc. 408.096584
Da, dev. -0.6 ppm.
4-(2-Chloro-4-methoxy-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-met-
hyl-pyrimidin-5-ylamine (Compound 2.10)
[0252] LC-ESI-HRMS of [M+H]+ shows 428.07825 Da. Calc. 428.078347
Da, dev. -0.2 ppm.
4-(3-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrimi-
din-5-ylamine (Compound 2.11)
[0253] LC-ESI-HRMS of [M+H]+ shows 382.09779 Da. Calc. 382.097332
Da, dev. 1.2 ppm.
4-(2-Chloro-4-trifluoromethyl-phenoxy)-6-(2-fluoro-4-trifluoromethyl-pheny-
l)-2-methyl-pyrimidin-5-ylamine (Compound 2.12)
[0254] LC-ESI-HRMS of [M+H]+ shows 466.05462 Da. Calc. 466.055166
Da, dev. -1.2 ppm.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-6-(4-methoxy-phenoxy)-2-methyl-pyrim-
idin-5-ylamine (Compound 2.13)
[0255] LC-ESI-HRMS of [M+H]+ shows 394.11735 Da. Calc. 394.117319
Da, dev. 0.1 ppm.
4-(3-Chloro-5-methoxy-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-met-
hyl-pyrimidin-5-ylamine (Compound 2.14)
[0256] LC-ESI-HRMS of [M+H]+ shows 428.0787 Da. Calc. 428.078347
Da, dev. 0.8 ppm.
4-(3-tert-Butyl-phenoxy)-6-(2-fluoro-4-trifl
uoromethyl-phenyl)-2-methyl-pyrim id in-5-ylamine (Compound
2.15)
[0257] LC-ESI-HRMS of [M+H]+ shows 420.16921 Da. Calc. 420.169354
Da, dev. -0.4 ppm.
4-(4-tert-Butyl-phenoxy)-6-(2-fl
uoro-4-trifluoromethyl-phenyl)-2-methyl-pyrimidin-5-ylamine
(Compound 2.16)
[0258] LC-ESI-HRMS of [M+H]+ shows 420.16943 Da. Calc. 420.169354
Da, dev. 0.2 ppm.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-(2-piperidin-1-yl-phenoxy-
)-pyrimidin-5-ylamine (Compound 2.17)
[0259] LC-ESI-HRMS of [M+H]+ shows 447.18022 Da. Calc. 447.180253
Da, dev. -0.1 ppm.
4-(2-Fluoro-phenoxy)-6-(2-fluoro-4-trifluoromethyl-phenyl)-2-methyl-pyrimi-
din-5-ylamine (Compound 2.18)
[0260] LC-ESI-HRMS of [M+H]+ shows 382.09758 Da. Calc. 382.097332
Da, dev. 0.6 ppm.
4-(2-Fluoro-4-trifluoromethyl-phenyl)-2-methyl-6-phenoxy-pyrimidin-5-ylami-
ne (Compound 2.19)
[0261] LC-ESI-HRMS of [M+H]+ shows 364.10723 Da. Calc. 364.106754
Da, dev. 1.3 ppm.
Example 3
Biological Activity
[0262] In this example the positive modulation of wild-type nAChR
.alpha.7 receptors by the compounds of the invention was determined
using nAChR .alpha.7 receptors heterologously expressed in Xenopus
laevis oocytes.
[0263] The electrical current through the nAChR .alpha.7 channel
was measured using conventional two-electrode voltage clamp and
nAChR .alpha.7 currents were activated by applying pulses of
agonist-containing solution onto the nAChR .alpha.7 expressing
oocyte.
[0264] In brief, the oocytes were placed in a recording chambers
and continuously super-fused with an Oocyte Ringer (OR) solution
containing 90 mM NaCl, 2.5 mM KCl, 2.5 mM CaCl.sub.2, 1 mM
MgCl.sub.2 and 5 mM HEPES (pH adjusted to 7.4). The oocytes were
clamped at -60 mV and currents were induced by applying 20 s pulses
of 100 .mu.M acetylcholine dissolved in OR. The intervals between
the acetylcholine applications were 5 minutes, during which the
oocytes were washed with OR. The first three applications were
control applications to insure a constant response level of 100
.mu.M acetylcholine. For the subsequent test applications,
increasing concentrations (0.01-31.6 .mu.M) of the test compound
were applied 30 s before and during the acetylcholine (100 .mu.M)
application, which caused a robust increase in the
acetylcholine-induced current amplitude.
[0265] The positive modulation in the presence of Compound was
calculated as (test-control)/control.times.100% and the
concentration response curve for this positive modulation was
fitted to the sigmoidal logistic equation:
I=I.sub.max/(1+(EC.sub.50/[compound]).sup.n),
where I.sub.max represents the maximal modulation of the control
response, EC.sub.50 is the concentration causing a half maximal
response, and n is the slope coefficient.
[0266] Calculated EC.sub.50 and I.sub.max values are presented in
the table below.
[0267] This is an indication of a biological activity as potent
modulators of the nicotinic acetylcholine oc7 receptor subtype.
TABLE-US-00001 Compound EC.sub.50 (.mu.M) I.sub.max (%) 1.1 2 1.2
23 391 1.3 2.3 1123 1.5 6.6 137 1.6 129 1.8 6.8 237 1.9 6.9 527
1.10 0.24 631 1.11 22 1.12 9.9 184 1.13 54 848 1.14 3 1.16 4.9 495
1.27 3.4 503 1.29 9.4 297 1.31 5.7 193 1.32 9.8 245 1.33 1.1 11
1.34 4.3 148 2.1 19 2.2 6.6 119 2.3 15 104 2.9 0.74 35 2.13 6
42
* * * * *